The Matrix Metalloproteinase System: Changes, Regulation, and Impact throughout the Ovarian and Uterine Reproductive Cycle (original) (raw)
Related papers
Cyclic Changes in the Matrix Metalloproteinase System in the Ovary and Uterus1
Biology of Reproduction, 2001
With each estrous or menstrual cycle, extensive alterations occur in the extracellular matrix and connective tissue of the ovary and uterus. In the ovary, these changes occur during follicular development, breakdown of the follicular wall and extrusion of the oocyte, as well as during the formation and regression of the corpus luteum. In the uterus, the endometrium undergoes dramatic connective tissue turnover associated with tissue breakdown and subsequent regrowth during each menstrual cycle. These changes in the ovarian and uterine extracellular architecture are regulated, in part, by the matrix metalloproteinase (MMP) system. This system is comprised of both a proteolytic component, the MMPs, and associated inhibitors, and it is involved in connective tissue remodeling processes throughout the body. The current review highlights the key features of the MMP system and focuses on the changes in the MMPs and the tissue inhibitors of metalloproteinases during the dynamic remodeling that takes place in the ovary and uterus during the estrous and menstrual cycles.
The role of metalloproteinases in endometrial remodelling during menstrual cycle
Ginekologia Polska
Endometrium is the only tissue in the human body subject to cyclic transformations under the influence of ovarian steroid hormones. As estradiol and progesterone balance throughout the physiological menstrual cycle changes, so does the expression of metalloproteinases (MMPs). These endopeptides are responsible for keeping the balance between the process of synthesis and degradation of extracellular matrix proteins. Thus, MMP's take part in sustaining physiological stability of the endometrium. A number of MMPs found in the endometrial tissue and their activity is related to menstrual cycle phase. This paper is an up-to-date review of literature of Medline database. The search was conducted for key words including "matrix metalloproteinases", "MMPs", "TIMPs" and "tissue inhibitors of metalloproteinases". Over 1092 publications regarding interdependence and interplay between ovarian hormones and the role of various MMPs and their inhibitors in normal endometrial remodelling and in pathological conditions were analysed and critically reviewed.
The role of the matrix metalloproteinases in human endometrial and ovarian cycles
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2003
The matrix metalloproteinases (MMPs) are part of an expanded family of proteins called the astacin family of zinc metalloproteinases. The MMPs, probably balanced by their tissue inhibitors of metalloproteinases (TIMPs), are essential effectors of developmental processes participating in cell migration, cell proliferation, apoptosis and tissue morphogenesis. The MMPs regulate the function of biologically active molecules as well as fulfilling an important role in endothelial cell invasion, angiogenesis and in tumor progression. The dynamic normal physiology of the human reproductive system involves almost all of the above-mentioned aspects of MMPs activity. This review presents and discusses new insights into the role of MMPs, and their TIMPs, in human endometrial cycle and ovarian function. #
Biology of Reproduction, 2003
The cyclic growth, differentiation, and cell death of endometrium represents the most dynamic example of steroid-driven tissue turnover in human adults. Key effectors in these processes-matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs)-are regulated by ovarian steroids and, locally, by cytokines. We used reverse transcription-polymerase chain reaction to evaluate the expression of both transcriptionally regulated molecules such as estrogen receptor-␣, progesterone receptor, and prolactin and a large array of MMPs and TIMPs (MMP-). Altogether, three distinct patterns of MMP and two patterns of TIMP expression were detected in cycling endometrium: 1) MMPs restricted to the menstrual period ; 2) MMPs and TIMPs expressed throughout the cycle (MMP-2, MT1-MMP, MT2-MMP, MMP-19, TIMP-1, and TIMP-2); 3) MMPs predominantly expressed during the proliferative phase (MMP-7, MMP-11, MMP-26, and MT3-MMP); and 4) TIMP-3, which, contrary to the other TIMPs, shows significant modulations, with maximum expression during the late secretory and menstrual phases. These specific patterns of MMP expression associated with each phase of the cycle may point to specific roles in the processes of menstruation, housekeeping activities, angiogenesis, tissue growth, and extracellular matrix remodeling.
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2012
When abundant and activated, matrix metalloproteinases (MMPs, or matrixins) degrade most, if not all, constituents of the extracellular matrix (ECM). The resulting massive tissue breakdown is best exemplified in humans by the menstrual lysis and shedding of the endometrium, the mucosa lining the uterus. After menstruation, MMP activity needs to be tightly controlled as the endometrium regenerates and differentiates to avoid abnormal tissue breakdown while allowing tissue repair and fine remodelling to accommodate implantation of a blastocyst. This paper reviews how MMPs are massively present and activated in the endometrium at menstruation, and how their activity is tightly controlled at other phases of the cycle. Progesterone represses expression of many but not all MMPs. Its withdrawal triggers focal expression of MMPs specifically in the areas undergoing lysis, an effect mediated by local cytokines such as interleukin-1α, LEFTY-2, tumour necrosis factor-α and others. MMP-3 is selectively expressed at that time and activates proMMP-9, otherwise present in latent form throughout the cycle. In addition, a large number of neutrophils loaded with MMPs are recruited at menstruation through induction of chemokines, such as interleukin-8. At the secretory phase, progesterone repression of MMPs is mediated by transforming growth factor-β. Tissue inhibitors of metalloproteinases (TIMPs) are abundant at all phases of the cycle to prevent any undue MMP activity, but are likely overwhelmed at menstruation. At other phases of the cycle, MMPs can elude TIMP inhibition as exemplified by recruitment of active MMP-7 to the plasma membrane of epithelial cells, allowing processing of membrane-associated growth factors needed for epithelial repair and proliferation. Finally, receptor-mediated endocytosis through low density lipoprotein receptor-related protein-1 (LRP-1) efficiently clears MMP-2 and -9 at the proliferative and secretory phases. This mechanism is probably essential to prevent any excessive ECM degradation by the active form of MMP-2 that is permanently present. However, shedding of the ectodomain of LRP-1 specifically at menstruation prevents endocytosis of MMPs allowing full degradation of the ECM. Thus endometrial MMPs are regulated at the levels of transcription, release from infiltrating neutrophils, activation, binding to the cell membrane, inhibition by TIMPs and endocytic clearance by LRP-1. This allows tight control during endometrial growth and differentiation but results in a burst of activity for menstrual tissue breakdown. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
Folia Histochemica Et Cytobiologica, 2018
Introduction. Endometrium undergoes regular, cyclic tissue remodeling mostly associated to the endocrine system status. It is well-known fact that steroid hormones are strongly responsible for changes in endometrium. The precise mechanism of their action is still under investigation. The aim of the study was to evaluate the expression of metalloproteinases 2 and 7 (MMP-2,-7) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in human endometrium in relation to serum concentrations of estradiol and progesterone during different phases of menstrual cycle. Material and methods. The study material consisted of 52 biopsy samples; 12 obtained in the proliferative phase, 11 in the secretory phase and 29 during menstruation. Expression of MMP-2, MMP-7 and TIMP-1 was assessed by immunohistochemistry. Serum concentrations of estradiol and progesterone at time of biopsy were evaluated by immunochemistry assay. Results of the study were statistically assessed by linear regression model. Results. Increased serum concentration of estradiol was associated with increased MMP-2 expression in proliferative phase but decreased in secretory phase and during menstruation. No significant relationship was found between progesterone concentration and MMP-2 expression. Moreover, no difference in the expression of MMP-7 and TIMP-1 in the endometrium in relation to hormone levels and menstrual cycle phases were observed. Conclusions. The results of the study indicate that estradiol influence MMP-2 expression in the endometrium depends on the phase of menstrual cycle. Such relationships were not found for MMP-7 and TIMP-1 and further tests clarifying association between estradiol and MMPs are needed.
Annals of the New York Academy of Sciences, 2002
The human endometrium exhibits regular cycles of growth, differentiation, and breakdown in response to changing levels of ovarian steroids. Following the tissue loss and repair processes of menstruation, rising levels of estradiol initiate a development-like process leading to a complete restructuring of the endometrial surface. In contrast, while under the predominate influence of progesterone, proliferation declines as cell-specific differentiation prepares the endometrium for pregnancy over a 5-to 6-day period. In the absence of nidation, steroid support is lost; the endometrial surface begins a complex process of tissue breakdown and bleeding, producing a viscous mixture of cellular debris within a bloody menstrual effluent. Although most of the menstrual fluid exits the body, reflux of some material occurs in most women, providing a poorly understood opportunity for ectopic endometrial growth and establishment of the disease endometriosis. The cyclic restructuring of the endometrium requires numerous matrix metalloproteinases (MMPs) that mediate normal and pathological tissue turnover throughout the reproductive tract. The expression of multiple MMPs facilitates degradation of extracellular matrix during growth-related remodeling as well as tissue breakdown at the time of menstruation. However, these enzymes are absent during the early and midsecretory phase and the suppression of endometrial MMPs remains important to maintaining the integrity of the endometrium during the highly invasive events required to establish a normal hemochorial placenta. Several research groups have suggested that steroid-mediated expression and action of MMPs during the menstrual cycle may provide a key mechanistic link between endometrial turnover and the invasive processes necessary for establishment of endometriosis.
Human Reproduction, 1999
Remodelling of endometrial tissues is fundamental to the cyclical changes that occur during the menstrual cycle, implantation and, in the absence of pregnancy, at menstruation. The enzyme matrix metalloproteinase-9 (MMP-9) is recognized as important in these processes but its regulation is not well defined. These studies have demonstrated that MMP-9 activity is present in the endometrium and exhibits cyclical changes in its distribution in the glandular and stromal cells. MMP-9 protein is present throughout the cycle with highest expression, as determined by semiquantitative analysis of specific MMP-9 immunoreactivity, in glandular cells during the mid secretory phase. A similar distribution was observed in first trimester decidua. In women with a levonorgestrel intrauterine system (LNG-IUS), which delivers high local concentrations of progestagen to the uterine cavity, MMP-9 is highly expressed in both endometrial glandular and stromal cells, and in the vasculature (in endothelial and perivascular cells). It can be concluded that MMP-9 is stimulated directly or indirectly by progesterone. Furthermore, MMP-9 may play a role in the remodelling of the endometrium that occurs during the menstrual cycle and in the aetiology of the morphological changes and breakthrough bleeding associated with long-term progestagen administration via a LNG-IUS. Key words: contraception-LNG/endometrium/matrix metalloproteinases/menstruation/tissue remodelling by guest on November 9, 2015 http://humrep.oxfordjournals.org/
Expression of Metalloproteinases and Their Inhibitors in Blood Vesselsin Human Endometrium
Biology of Reproduction, 1999
Matrix metalloproteinases (MMPs) are zinc-requiring enzymes that can degrade components of the extracellular matrix and that are implicated in tissue remodeling. Their role in the onset of menstruation in vivo has been proven; however, the expression and functions of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in vascular structures are poorly understood. We determined by immunocytochemistry, using characterized monoclonal antibodies, the distribution of MMPs and of their inhibitors TIMP-1 and TIMP-2 in the endometrium during the menstrual cycle. MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 had differing distributions and patterns of expression. In addition to the localization of MMP-9 in the epithelium and of MMP-2, MMP-3, and MMP-1 in the stromal tissue, these MMPs were detected in the vascular structures. MMP-2 (72-kDa gelatinase) and tissue inhibitors TIMP-1 and TIMP-2 were detectable in vessels throughout the cycle. In contrast, MMP-3 (stromelysin-1) was detected only in late-secretory and menstrual endometrial vessels, while MMP-9 (92-kDa gelatinase) was detected in spiral arteries during the secretory phase and in vascular structures during the midfollicular and menstrual phases. The expression of MMP-2 and MMP-9 in endometrial vessels during the proliferative and secretory periods suggests their relationship to vascular growth and angiogenesis. The pronounced expression of MMP-3 (stromelysin-1) in the vessels situated in the superficial endometrial layer during menses suggests that this metalloproteinase initiates damage in the vascular wall during menstrual breakdown. The finding of an intense expression of TIMP-1 and TIMP-2 in the vessels delineating necrotic from non-necrotic areas during menses also suggests that they could limit tissue damage, allowing regeneration of the endometrium after menses. These data indicate that, in addition to expression in epithelial cells and stromal tissue, MMPs are expressed in endometrial vascular cells in a cycle-specific pattern, consistent with regulation by steroid hormones and with specific roles in the vascular remodeling processes occurring in the endometrium during the cycle.